Genotoxic effects of high-energy iron particles in human lymphoblasts differing in radiation sensitivity.

The effects of (56)Fe particles and (137)Cs gamma radiation were compared in TK6 and WTK1 human lymphoblasts, two related cell lines which differ in TP53 status and in the ability to rejoin DNA double-strand breaks. Both cell lines were more sensitive to the cytotoxic and clastogenic effects of (56)Fe particles than to those of gamma rays. However, the mutagenicity of (56)Fe particles and gamma rays at the TK locus was the same per unit dose and was higher for gamma rays than for (56)Fe particles at isotoxic doses. The respective RBEs for TK6 and WTK1 cells were 1.5 and 1.9 for cytotoxicity and 2.5 and 1.9 for clastogenicity, but only 1 for mutagenicity. The results indicate that complex lesions induced by (56)Fe particles are repaired less efficiently than gamma-ray-induced lesions, leading to fewer colony-forming cells, a slightly higher proportion of aberrant cells at the first division, and a lower frequency of viable mutants at isotoxic doses. WTK1 cells (mutant TP53) were more resistant to the cytotoxic effects of both gamma rays and (56)Fe particles, but showed greater cytogenetic and mutagenic damage than TK6 cells (TP53(+)). A deficiency in the number of damaged TK6 cells (a) reaching the first mitosis after exposure and (b) forming viable mutants can explain these results.     

Karyotypes of human lymphocytes exposed to high-energy iron ions

Chromosomal aberrations were analyzed using multicolor fluorescence in situ hybridization (mFISH) in human peripheral blood lymphocytes after in vitro exposure to gamma rays or accelerated (56)Fe ions (1 GeV/nucleon, 145 keV/microm) at Brookhaven National Laboratory (Upton, NY). Doses of 0.3 and 3 Gy were used for both radiation types. Chromosomes were prematurely condensed by a phosphatase inhibitor (calyculin A) to avoid the population selection bias observed at metaphase as a result of the severe cell cycle delays induced by heavy ions. A total of 1053 karyotypes (G(2) and M phases) were analyzed in irradiated lymphocytes. Results revealed different distribution patterns for chromosomal aberrations after low- and high-LET radiation exposures: Heavy ions induced a much higher fraction of cells with multiple aberrations, while the majority of the aberrant cells induced by low doses of gamma rays contained a single aberration. The high fraction of complex-type exchanges after heavy ions leads to an overestimation of simple-type asymmetrical interchanges (dicentrics) from analysis of Giemsa-stained samples. However, even after a dose of 3 Gy iron ions, about 30% of the cells presented no complex-type exchanges. The involvement of individual chromosomes in exchanges was similar for densely and sparsely ionizing radiation, and no statistically significant evidence of a nonrandom involvement of specific chromosomes was detected.     

Relationship between linear energy transfer and behavioral toxicity in rats following exposure to protons and heavy particles.

Rats were exposed to protons (155 MeV) or to helium (165 MeV/amu), neon (522 MeV/amu) or argon (670 MeV/amu) particles to evaluate the behavioral toxicity of these types of radiations. Behavioral toxicity was assessed using the conditioned taste aversion paradigm. Exposure to all types of radiation produced dose-dependent increases in the intensity of the acquired taste aversion. However, the intensity of the aversions, measured as the dose that produced a 50% decrease in the intake of the sucrose-conditioned stimulus, did not show significant variation as a function of the linear energy transfer (LET) of the radiation. The results are discussed in terms of the relationship between LET and behavioral toxicity.     

Reduction of 3-methoxytyramine concentrations in the caudate nucleus of rats after exposure to high-energy iron particles: evidence for deficits in dopaminergic neurons

Exposure to low doses of high-energy iron particles can alter motor behavior. The ability of rats to hang from a wire has been reported to be significantly degraded after exposure to doses as low as 0.5 Gy. In addition, deficits in the ability of acetylcholine to regulate dopamine release in the caudate nucleus (an area in the brain important for motor function) have been found. The concentrations of 3-methoxytyramine (3-MT), a metabolite of dopamine whose concentrations reflect dopamine release in vivo, were measured after rats were exposed to different doses of high-energy iron particles to gain further information about the effect of radiation on the dopaminergic system. Concentrations of 3-MT were significantly reduced 3 days after exposure to 5 Gy but returned to control values by 8 days. After 6 months, concentrations were again less than control values. Exposure to 5 Gy of high-energy electrons or gamma photons had no effect 3 days after exposure. Very high doses of electrons were needed to alter 3-MT concentrations. One hundred grays of electrons decreased 3-MT 30 min after irradiation but levels returned to control values by 60 min. Gamma photons had no effect after doses up to 200 Gy. These results provide further evidence that exposure to heavy particles can degrade motor behavior through an action on dopaminergic mechanisms and that this can occur after doses much lower than those needed for low-LET radiation.     

An assessment of the genetic toxicity of atrazine: Relevance to human health and environmental effects

The genetic toxicity of atrazine, a member of the s-triazine herbicides, was reviewed with the objective of classifying the chemical. Atrazine has been subjected to a broad range of genetic tests with predominantly negative results. Some publications, specifically those measuring dominant lethality in mice and bone marrow clastogenicity in rodents, reported conflicting results across two or more independent tests. Two approaches were employed to evaluate and interpret the results. The first approach attempts to classify each type of genetic endpoint as positive or negative and resolve test conflicts by critical assessment of the study and detailed data. This is the more traditional “expert judgment” approach to hazard assessment. The second approach employs a computer-assisted weight-of-evidence method of data analysis. This approach does not require resolution of conflicts but uses all data sets to arrive at a classification of hazard. The first approach was able to resolve some conflicts but not all. Use of the “expert judgement” results in an equivocal conclusion and classification. Use of the weight-of-evidence method resulted in a conclusion that atrazine does not pose a mutagenic hazard. The weight-of-evidence scheme is proposed to be a more practical and relevant approach for assessing complex data sets.     

An assessment of the toxicity of metals to Pseudomonas aeruginosa PU21 (Rip64)

The toxicity of Co(II), Mn(II), Cd(II), and Zn(II) for Pseudomonas aeruginosa PU21, a Hg(II)-hyperresistant strain containing the mercury resistance mer operon, was determined. The metal tolerance of PU21 was strongly influenced by environmental conditions (e.g., existing metal, medium composition). Dose-response analysis on chronic and acute toxicity (e.g., EC(20), median effective dose EC(50), and slope factor B) of divalent cobalt, manganese, cadmium, and zinc cations in LB medium amended with citric acid phosphate buffered saline (CAPBS) suggested a toxicity series of Co > Mn approximately Zn > Cd for EC(50). In contrast, excluding the likely precipitate of Zn(II), the toxicity ranking in phosphate-buffered saline (PBS)-amended LB medium was Co > Cd > Mn. The metal toxicity in PBS, irrespective of metals, was greater than that in CAPBS. This might be attributed to the presence of citric acid in CAPBS as a chelating ligand donating electrons to hold free metals (e.g., Cd(2+), Zn(2+) tetrahedral ML(4) complex). The toxicity assessment established viable operation ranges (ca. 相似文献   

An effective assessment of simvastatin-induced toxicity with NMR-based metabonomics approach

Background

Simvastatin, which is used to control elevated cholesterol levels, is one of the most widely prescribed drugs. However, a daily excessive dose can induce drug-toxicity, especially in muscle and liver. Current markers for toxicity reflect mostly the late stages of tissue damage; thus, more efficient methods of toxicity evaluation are desired.

Methodology/Principal Findings

As a new way to evaluate toxicity, we performed NMR-based metabonomics analysis of urine samples. Compared to conventional markers, such as AST, ALT, and CK, the urine metabolic profile provided clearer distinction between the pre- and post-treatment groups treated with toxic levels of simvastatin. Through multivariate statistical analysis, we identified marker metabolites associated with the toxicity. Importantly, we observed that the treatment group could be further categorized into two subgroups based on the NMR profiles: weak toxicity (WT) and high toxicity (HT). The distinction between these two groups was confirmed by the enzyme values and histopathological exams. Time-dependent studies showed that the toxicity at 10 days could be reliably predicted from the metabolic profiles at 6 days.

Conclusions/Significance

This metabonomics approach may provide a non-invasive and effective way to evaluate the simvastatin-induced toxicity in a manner that can complement current measures. The approach is expected to find broader application in other drug-induced toxicity assessments.     

An approach for the assessment of risk from chronic radiation to populations of phytoplankton and zooplankton

A conceptual model of the effects of chronic radiation on a population of phytoplankton and zooplankton in an oceanic nutrient layer is presented. The model shows that there are distinct threshold dose rates at which the different plankton populations become unsustainable. These are 10,400 μGy h⁻¹ for phytoplankton and 125 μGy h⁻¹ for zooplankton. Both these values are considerably greater than the current screening values for protection of 10 μGy h⁻¹. The model highlights the effects of predator–prey dynamics in predicting that when the zooplankton is affected by the radiation dose, the phytoplankton population can increase. In addition, the model was altered to replicate the dose rates to the plankton of a previous ERICA Irish Sea assessment (24 μGy h⁻¹ for zooplankton and 430 μGy h⁻¹ to phytoplankton). The results showed only a 10% decrease in the zooplankton population and a 15% increase in the phytoplankton population. Therefore, at this level of dose, the model predicts that although the dose rate exceeds the guideline value, populations are not significantly affected. This result highlights the limitations of a single screening value for different groups of organisms.     

N-terminal sequences of oat avenins compared to other cereal prolamins

Like the alcohol-soluble seed storage proteins (also called prolamins) of other cereals, avenins, the oat prolamins, are a series of polymorphic molecules belonging to a multigenic family stored within the protein bodies of the starchy endosperm. Nevertheless, they exhibit some pecularities: among the seed storage proteins, their proportion is low compared to prolamins from other cereal species; their net charge is higher; the amount of Gln + Pro only reaches 49 mol%; they are less polymorphic. We have isolated and purified several avenins and sequenced their N-terminal end. The microheterogeneity and the pecularity of avenins are revealed by the comparison of the N-terminal sequences. Like other prolamins, they exhibit tandem repeats; these repetitive peptides are slightly different from those of other prolamins of the Festucoideae, and the repetition begins earlier in the sequence. As for prolamins from other species, their predicted secondary structure reveals successive beta-turns which might be arranged in a pseudo-helix structure.     

The toxicity of sanguinarine compared to a number of other DNA-tropic compounds for ethidium bromide-sensitive and -resistant transformed murine fibroblasts in culture

A natural DNA-intercalator plant benzo-c-phenanthridine alkaloid sanguinarine is more toxic for mouse transformed fibroblast L-cells in culture than synthetic DNA-intercalator ethidium bromide (EtB) and alkaloid berberine. Dimidium bromide is also an inhibitor of the L-cell growth. In assay conditions, growth of L-cells is stopped by 1.5 x 10(-5) M of sanguinarine. Lebr-625 cells, resistant to 25 micrograms/ml of EtB, have sanguinarine sensitivity close to that of L-cells, but Lebr-625 cells are resistant to dimidium bromide. Sanguinarine is more toxic for L-cells in culture than the anticancer drug cis-PtNH3)2Cl2. Trans-Pt(NH3)2Cl2 is less toxic for these cells. The strong toxicity of sanguinarine for L- and Lebr-625 cells in culture, as compared to other DNA-complexing drugs, seems to be associated with the wide range of potential cell targets for sanguinarine influence. Besides the inhibition of nucleic acid metabolism reactions, characteristic of DNA-intercalators, and disruption the mitochondrial ATP synthesis, also characteristic of organic heterocyclic cationic molecules of DNA-intercalators, sanguinarine can modify the thiol groups of enzymes including SH-sensitive membrane-bound Na+, K(+)-ATPase of cerebral cortex and Ca2(+)-ATPase of skeletal muscle sarcoplasmic reticulum fragments.     

Physiological and behavioral responses to strangers compared to friends as a source of disgust

Known as the source effect, feelings of disgust have been found to differ depending on the source of the disgusting material, with that emanating from oneself and familiar others eliciting less disgust than that of strangers. We tested the source effect on self-report of disgust feelings (Study 1), physiological response in heart rate (Study 2), and behavioral response in terms of approach–avoidance movement (Study 3). The results showed significantly higher levels of disgust feelings, more reduced heart rates, and faster avoidance behavior when processing disgusting material associated with strangers compared to that of familiar persons. Together these findings support the evolutionary view that disgust, as part of the human behavioral immune system to drive avoidance from disease-carrying agents, will likely be activated more intensely and quickly in response to unfamiliar as compared to familiar conspecifics who carry common germs more defendable by our shared physical immunity.     

Comparative effects of exposure to high-energy electrons and gamma radiation on active avoidance behaviour

The effect of two types of ionizing radiation was examined on active avoidance behaviour. Male Sprague-Dawley rats were trained to avoid footshock by jumping onto a retractable ledge. When irradiated with high-energy electrons or gamma photons, their performance was degraded in a dose-dependent manner. However, electrons were 1.6 times as effective as gamma photons with ED50s of 62 and 102 Gy, respectively. All animals recovered within 24 min for all doses used. The data suggest that different types of ionizing radiation may not be equivalent when assessing their effect on behaviour.     

Genetic and biochemical analysis of high iron toxicity in yeast: iron toxicity is due to the accumulation of cytosolic iron and occurs under both aerobic and anaerobic conditions

Iron storage in yeast requires the activity of the vacuolar iron transporter Ccc1. Yeast with an intact CCC1 are resistant to iron toxicity, but deletion of CCC1 renders yeast susceptible to iron toxicity. We used genetic and biochemical analysis to identify suppressors of high iron toxicity in Δccc1 cells to probe the mechanism of high iron toxicity. All genes identified as suppressors of high iron toxicity in aerobically grown Δccc1 cells encode organelle iron transporters including mitochondrial iron transporters MRS3, MRS4, and RIM2. Overexpression of MRS3 suppressed high iron toxicity by decreasing cytosolic iron through mitochondrial iron accumulation. Under anaerobic conditions, Δccc1 cells were still sensitive to high iron toxicity, but overexpression of MRS3 did not suppress iron toxicity and did not result in mitochondrial iron accumulation. We conclude that Mrs3/Mrs4 can sequester iron within mitochondria under aerobic conditions but not anaerobic conditions. We show that iron toxicity in Δccc1 cells occurred under both aerobic and anaerobic conditions. Microarray analysis showed no evidence of oxidative damage under anaerobic conditions, suggesting that iron toxicity may not be solely due to oxidative damage. Deletion of TSA1, which encodes a peroxiredoxin, exacerbated iron toxicity in Δccc1 cells under both aerobic and anaerobic conditions, suggesting a unique role for Tsa1 in iron toxicity.     

Selective toxicity of wyerone and other phytoalexins to gram-positive bacteria

The antibacterial activities of isoflavonoid (kievitone and phaseollin), flavonoid (hydroxyflavans), furanoacetylenic (wyerone), and sesquiterpenoid (capsidiol and rishitin), phytoalexins against eight Gram-negative and six Gram-positive bacteria were examined using the paper-disc antibiotic assay method. With the exception of capsidiol, which was inactive at the highest concentration tested (200,μg/disc) all of the phytoalexins were selectively toxic towards Gram-positive species. Wyerone and kievitone were generally more toxic than other phytoalexins; rishitin was the least active inhibitor.     

An assessment of the potential testicular toxicity of 10 pesticides using the mouse-sperm morphology assay

Dinitrobutylphenol, chlorbenzilate, atrazine, Ordram, Telone (dichloropropene), pentachlorophenol (technical and reagent grades), Benomyl, DBCP (dibromochloropropane), and carbaryl were tested over a range of 7 doses in the mouse to assess their testicular toxicity. Measures of potential toxicity were sperm morphology, sperm counts and testicular weights. Each pesticide was injected intra-peritoneally in a single dose on each of 5 days. Testicular toxicity was assessed at 35 days. None of the pesticides tested, including the known human male testicular toxin, DBCP, produced statistically significant differences in the parameters from vehicle-injected controls.     

Research needs to improve risk assessment of fiber toxicity

Risk characterization of exposure to toxic compounds requires information on the intrinsic toxic properties, including toxic mechanism and toxicokinetics, on dose response at the most critical targets for identification of the NOEL or for extrapolation from high to low dose, and on human exposure. Abundant information is available on the intrinsic properties of MMMF, on the three D's (dose, dimension, durability) and on the toxic mechanisms. However, only a few of these studies provide information on the dose response of the effects or of the mechanisms investigated. Moreover, in many cases single high doses exceeding the MTD have been applied and are difficult to interpret for lower exposure scenarios. Risk characterization is further hampered by the still open question whether MMMF are directly genotoxic or induce secondary genotoxicity via inflammation. Finally, there is disagreement about the relevance of animal studies on MMMF for humans and thus about the most rational extrapolation of the dose response of toxic effects observed in animals to man. These deficits are briefly described and discussed from a toxicological point of view.     

Dual-level toxicity assessment of biodegradable pesticides to aquatic species

The use of ecological models to assess the effects of pesticides on the structure and function of aquatic ecosystems is of growing interest. Of utmost concern is assessment of pesticides that have the potential to biodegrade into metabolites that are as toxic as the parent pesticide. In this work, a mathematical model to predict and evaluate the effect of two pesticides on the population of aquatic biospecies where both pesticides are bio-available in water and sediments with one of the pesticides capable of biodegrading into the other but not vice versa is formulated and analyzed. Conditions for nonlinear stability, instability and Hopf-bifurcation are obtained. The model undergoes a Hopf-bifurcation when the rate of discharge of pesticides crosses a critical value, so that the population of the aquatic species follows an oscillatory pattern. Four hypotheses involving the concentration of the pesticides and the population of the aquatic species where qualitatively investigated: the aquatic species will completely die out with time, the population of the aquatic biospecies will remain under certain conditions, the pesticide will continually remain in water and there will be a periodic variation in the population of the aquatic species over time. Results also indicate that the biodegradation potential of one of the pesticides had significant effect on the population dynamics of the aquatic species.